Abstract
There is sufficient evidence that statins have a protective role against breast cancer proliferation and recurrence, but treatment predictive biomarkers are lacking. Breast cancer cell lines displaying diverse sensitivity to atorvastatin were subjected to global transcriptional profiling and genes significantly altered by statin treatment were identified. Atorvastatin treatment strongly inhibited proliferation in estrogen receptor (ER) negative cell lines and a commensurate response was also evident on the genome-wide transcriptional scale, with ER negative cells displaying a robust deregulation of genes involved in the regulation of cell cycle progression and apoptosis. Interestingly, atorvastatin upregulated genes involved in the cholesterol biosynthesis pathway in all cell lines, irrespective of sensitivity to statin treatment. However, the level of pathway induction; measured as the fold change in transcript levels, was inversely correlated to the effect of statin treatment on cell growth. High expression of cholesterol biosynthesis genes before treatment was associated with resistance to statin therapy in cell lines and clinical biopsies. Furthermore, high expression of cholesterol biosynthesis genes was independently prognostic for a shorter recurrence-free and overall survival, especially among ER positive tumors. Dysregulation of cholesterol biosynthesis is therefore predictive for both sensitivity to anti-cancer statin therapy and prognosis following primary breast cancer diagnosis.
Highlights
There is a continuous search for complementary treatments, which can act in concert with already approved anti-cancer therapeutics to prevent or delay the development of therapy resistance and prolong the survival of patients diagnosed with cancer
We investigated the effect of atorvastatin treatment on the proliferation rate of the four selected breast cancer cell lines, representing different breast cancer molecular subtypes
MDA-MB-231 (ER-/PR-/ HER2-) cells were extremely sensitive to statin treatment with less than 30% of cells surviving after 72 hours exposure to 2 μM of atorvastatin (Supplementary Figure S1A)
Summary
There is a continuous search for complementary treatments, which can act in concert with already approved anti-cancer therapeutics to prevent or delay the development of therapy resistance and prolong the survival of patients diagnosed with cancer. Statins have received recognition as potential anti-cancer agents because several epidemiological studies have confirmed an association between statin use and a decreased risk of disease recurrence following adjuvant treatment [1,2,3,4]. Pre-clinical studies indicate that statins can decrease breast cancer cell growth and induce apoptosis in various experimental models [5,6,7,8]. We and others have reported results from pre-surgical “window-ofopportunity” clinical trials in breast cancer confirming that statins can decrease tumor proliferation and induce apoptotic cell death [9, 10]. Considering the potential benefits of adding statins (which are well tolerated, safe and inexpensive drugs) to established breast cancer therapeutic regimens, there is a need for clinical trials to prospectively evaluate the role of statins in breast cancer therapy. Treatment predictive markers to select patients most likely to derive benefit from statin therapy will be of great value to effectively design such studies
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